title: The winged helix transcription factor Foxa3 regulates adipocyte differentiation and depot-selective fat tissue expansion.
abstract: Conversion of mesenchymal stem cells into terminally differentiated adipocytes progresses sequentially through regulated transcriptional steps. While it is clear that the late phases of adipocyte maturation are governed by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), less is known about the transcriptional control of the initial stages of differentiation. To identify early regulators, we performed a small interfering RNA (siRNA) screen of Forkhead-box genes in adipocytes and show here for the first time that the winged helix factor Foxa3 promotes adipocyte differentiation by cooperating with C/EBPβ and -δ to transcriptionally induce PPARγ expression. Furthermore, we demonstrate that mice with genetic ablation of Foxa3 have a selective decrease in epididymal fat depot and a cell-autonomous defect to induce PPARγ specifically in their visceral adipocytes. In obese subjects, FOXA3 is differentially expressed in visceral and subcutaneous adipose depots. Overall, our study implicates Foxa3 in the regulation of adipocyte differentiation and depot-selective adipose tissue expansion.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Xu
authors.forename: Valentine
authors.initials: V
authors.lastname: Panel
authors.forename: Xinran
authors.initials: X
authors.lastname: Ma
authors.forename: Chen
authors.initials: C
authors.lastname: Du
authors.forename: Lynne
authors.initials: L
authors.lastname: Hugendubler
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Alice
authors.initials: A
authors.lastname: Liu
authors.forename: Tracey
authors.initials: T
authors.lastname: McLaughlin
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mueller
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis; D000273:Adipose Tissue / Q000254:growth & development* / Q000378:metabolism; D000328:Adult; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C496506:Foxa3 protein, mouse; D047495:PPAR gamma; D051543:Hepatocyte Nuclear Factor 3-gamma; D051743:CCAAT-Enhancer-Binding Protein-delta